According to the Centers for Disease Control and Prevention, about 25 million Americans have asthma, and that number is increasing every year.

In the last 10 years, a number of new medications have become available. Collectively referred to as 'biologics,' these therapies are made to target very specific parts of the body and its immune system. Although they each have different targets, they all are designed to prevent the inflammation that leads to asthma exacerbation.

However, it appears their use so far is pretty low in the U.S., despite the number of people who likely could benefit from the drugs.

In a series of recent publications, a group of Mayo Clinic researchers describe trends and disparities in asthma biologic use in the United States. They used the OptumLabs Data Warehouse — a massive database containing deidentified pharmacy and medical claims that are linked electronic health records — to find out more about when and how asthma biologic therapies are being used, and how effective the different medications seem to be for patients.

The following five publications describe some of the research findings:

• Trends and Disparities in Asthma Biologic Use in the United States

In this retrospective study, the investigators examined the records of 2.01 million unique individuals treated for asthma between Jan. 2003 and June 2013. They then identified 6,651 people who filled at least one prescription for a biologic asthma medication — benralizumab, dupilumab, mepolizumab, omalizumab or reslizumab — during that time period. Of these, 4,779 patients received a biologic asthma medication for the first time.

The patients who received biologic therapies were mostly white, adult (ages 18-64), females, with a annual income of more than $75,000, and who saw a specialist to treat their asthma.

"Almost all of the asthma biologics prescribed in the U.S. are prescribed by specialists, and that those specialists were more accessible to certain groups of people than others," says Matthew Rank, M.D., the senior investigator for the asthma research.

"We also found low utilization rates for all the biologics, even omalizumab, which has been around several years longer than any of the others," he says. "Most of them are administered by a health care provider, and require specialized expertise to manage, as well as being high cost," Dr. Rank says.

"However, there is also a clear gap between the number of people receiving biologics and those we know of who would benefit from these therapies."

• Adherence to Asthma Biologics: Implications for Patient Selection, Step Therapy, and Outcomes

Many people can control their asthma by using inhaled corticosteroids. However, sometimes patients are unable to manage with steroids alone. Adding a biologic to their regimen can reduce asthma exacerbation rates substantially.

"We know that sometimes it is difficult for patients to keep up with their treatments as prescribed," says Dr. Rank. "This can cause treatment failure in the case of inhaled corticosteroids. We wanted to know if adherence to asthma biologics was similarly difficult for patients, and if there was any difference in outcomes."

Using the OptumLabs Data Warehouse, the team identified more than 3 million people with persistent asthma from Jan. 1, 2012, through Oct. 31, 2019, of which 23,000 received biologic asthma medication. They examined the fill rate of prescriptions for inhaled corticosteroids and rescue inhalers prior to and after introduction of biologics, as well as the subsequent fill rate of the new biologic therapy. This allowed the team to determine the proportion of days covered, or PDC, by each medication, for each patient. Higher PDC rates indicate patients are regularly taking their prescribed medications.

In the six months preceding their first biologic prescription, on average patients achieved 44% PDC with inhaled corticosteroids. In the first six months with a biologic, the mean PDC of the biologic was 76%. However, the PDC for the steroid actually dropped slightly to 40% while on the biologic.

Adherence to the biologic medication regimen seemed to be associated with a noticeable response to the treatment, i.e. less frequent exacerbations requiring emergency medical care or hospitalization. Higher biologic PDC, greater than or equal to 75%, was associated with higher inhaled corticosteroid PDC before and during biologic use. The team reviewed a number of other potential factors and found that several seemed to influence better adherence to the biologic, including:

• Older age and male
• No COPD or depression comorbidities
• Medicare Advantage insurance, compared to commercial insurance
• Pre-biologic PDC rates similarly high with inhaled corticosteroids

The investigators found a number of factors that made it more or less likely that people would consistently take their inhaled corticosteroids, before or after incorporating biologics. Any variances in continuation of inhaled corticosteroids didn't seem to affect whether or not patients experienced exacerbations requiring emergency care or hospitalization.

"People are more likely to adhere to biologics than their inhaled corticosteroids," says Dr. Rank. "We think this may be due to how these medicines are administered — less frequently and often under more direct medical supervision when given as an injection."

However, he notes that insurance coverage and the cost of treatment may be a significant reason that patients don't get, or maintain, biologic therapy.

• Persistence of asthma biologic use in a US claims database

In this study, the researchers examined whether people who are prescribed asthma biologics continue to take them once it appears their exacerbations have decreased substantially.

Guidelines recommend that biologics be prescribed to people with severe asthma who have poor control of their asthma when using the standard treatment of inhaled corticosteroids. Currently, it is recommended that a patient receive treatment initially for four to six months.

The investigators examined a cohort of 9,575 people with persistent asthma who started an asthma biologic. They found that between 48% and 64% remained on their biologic for at least six months or longer. Only 34% were still on biologic therapy after 12 months.

"We are trying to understand how long people use asthma biologics," says Dr. Rank. "We were surprised to learn that many patients were not on these medicines long enough to judge how well they are working.  This suggests that there are other factors, besides response to treatment, that are important in these decisions."

They found that there were more improvements over time for some people. This led the authors to conclude that there may be value in extending an initial trial period of asthma biologics based on clinical response of the individual rather than standard guidelines.

• Asthma Patients Who Stop Asthma Biologics Have a Similar Risk of Asthma Exacerbations as Those Who Continue Asthma Biologics

In this study, the investigators examined the records of 2,494 people, forming two groups of people with similar characteristics. Of these, 1,247 people who stopped use of asthma biologics after using them for 6 to 12 months, compared to 1,247 who continued using them for at least 18 months.

The researchers used the OptumLabs Data Warehouse to look at real world outcomes, comparing them to what has been observed in clinical trials of asthma biologics.

The researchers found that an increase in asthma exacerbations was infrequently observed among people who stopped taking the biologics. They found a similar rate of exacerbations among those who continued the therapy.

This suggests that stopping biologic therapy does not increase risk of exacerbation. Understanding this can help in clinician–patient decision making.

"There are currently no guidelines for patients and their health care providers for what to do when a patient is treated long term with asthma biologics," says Dr. Rank. "When should we stop asthma biologics?  How do we choose which patients who may be safe to stop?  In this study we found that many people were able to stop asthma biologics without a recurrence in asthma exacerbations.  This suggests that stopping asthma biologics is possible, but there is a lot more work to do in figuring out who are the best candidates for stopping and what is the best timing for stopping."

• Asthma biologic trial eligibility and real-world outcomes in the United States

In this study, the researchers were able to replicate clinical trial criteria from the trials used in gaining Food and Drug Administration (FDA) approval for the various asthma biologics.

They compared the outcomes of real-world patients who would have been eligible for the trials to those who would not have been eligible. The team used a set of 19 clinical trials covering each of the five biologic medications — benralizumab, dupilumab, mepolizumab, omalizumab or reslizumab — to identify eligible versus ineligible patients.

This type of research is important because eligibility and inclusion criteria for clinical trials are often very limiting, and racial and ethnic diversity is often low. This means that in a general population, a majority of people who might benefit from the medication are not represented in the trials, and therefore the effectiveness may not be the same. The investigators looked at the data of 9,783 people taking an asthma biologic. The investigators found that fewer than 1 in 10 people receiving biologics would have been eligible to participate in the clinical trial for the biologic they used.

Dr. Rank adds, "As health care providers, we ask ourselves, 'Will my patient who would not have qualified for the clinical trial still potentially benefit from this treatment?'"

"This is one of the important capabilities of the OptumLabs Data Warehouse — the ability to look at very large numbers of patients who actually receive the medicines in clinical practice.  The individuals may have many more comorbidities and different individual characteristics than you would see in a clinical trial. This type of research helps us understand how we should apply research evidence from clinical trials in clinical practice."

The team found that asthma exacerbations decreased in the 12 months after starting a biologic — for both those eligible and those ineligible for the trial of the medication they were taking. However, depending on the particular medication, the apparent effectiveness varied between the groups.

For omalizumab and dupilumab, eligible patients reduced their exacerbations more than that of the ineligible group. For the other medications, differences were not significant between the groups, although more research is needed as fewer patients have been prescribed the other asthma biologics.

Despite having data from a diverse group of nearly 10,000 patients, the authors note that for some of the trials they compared, none of the patients receiving that medication would have been eligible. And, for many, the number of eligible patients in the cohort was very small (less than 11), so any differences in outcomes were not able to be determined. They concluded that most of the people currently treated with asthma biologics in the U.S. would not have qualified for the clinical trials that led to the FDA approval of these medicines.

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This research was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (NIH R21 HL140287) and the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery.

Dr. Rank is a professor of medicine in the Mayo Clinic Alix School of Medicine and is chair of the Division of Allergy, Asthma, and Clinical Immunology at Mayo Clinic in Arizona. Until recently, he served as the medical director of the Kern Health Care Delivery Scholars Program — in which he was also part of the inaugural cohort.

The other researchers involved in these studies are:

• Jonathan Inselman
• Molly Jeffery, Ph.D.
• Regina Lam
• Jacob Maddux, M.D.
• Che Ngufor, Ph.D.
• Nilay Shah, Ph.D.

OptumLabs is a collaborative center for research and innovation co-founded by Optum Inc. and Mayo Clinic and focused on improving patient care and patient value. Mayo Clinic's connection to OptumLabs is overseen in the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Center research focuses on transforming clinical practice. Researchers seek to discover new ways to improve health; translate those discoveries into evidence-based, actionable treatments, processes and procedures; and apply this new knowledge to improve patient care.

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